RNA viruses are responsible for many diseases of man and animals. Examples of RNA viruses which are human pathogens include influenza virus, poliovirus, rhinovirus and HIV. A specific example of a pathogenic DNA virus which replicates via an essential RNA intermediate is hepatitis B virus (HBV).
Very few effective antiviral agents are currently available. Certain compounds which are moderately effective against HIV are deoxynucleoside analogues. These act by inhibiting HIV replication by acting as “chain terminators” i.e. causing termination of HIV reverse transcriptase-mediated DNA synthesis. However the efficacy of such drugs is limited because of the emergence of resistant strains of viruses. RNA viruses in general, and HIV in particular, have a very high mutation rate during replication, and this high mutation frequency enhances the likelihood of resistant strains emerging.
Recently the idea has developed that RNA viruses may be close to the “edge of viability”. That is, the mutation frequency of such viruses is so high that a comparatively modest increase in mutation frequency may be sufficient to render the great majority of the viral population non-viable, due to the presence of deleterious mutations at essential loci in the viral genome. This well-known concept is known as “error catastrophe” and results with the mutagen ribavirin in the context of poliovirus strongly suggest that the concept is well-founded (Crotty et al, 2000 Nature Medicine 6, 1375–1379; Crotty et al, 2001 Proc. Natl. Acad. Sci. USA 98, 6895–6900).
Loeb et al, (WO 98/18324 and U.S. Pat. No. 6,063,628) disclose the use of ribonucleoside analogues to increase the mutation rate in (and thereby inhibit the replication of) RNA viruses such as HIV or HCV. Loeb et al state that the ribonucleoside analogue may typically be an analogue of cytidine, uridine, adenosine or guanosine, but that analogues of cytidine or uridine (i.e. pyrimidine analogues) are preferred (U.S. Pat. No. 6,063,628; column 3 lines 44–45). Loeb et al do not specifically refer to many purine nucleoside analogues, but adenosine analogues specifically mentioned include: 1,N6-ethenoadenosine, 3-methyladenosine and N6-methyladenosine. Guanosine analogues specifically mentioned include 8-hydroxyguanosine, O6-methylguanosine, O6-ethylguanosine, O6-isopropylguanosine, 3,N2-ethenoguanosine, O6-alkylguanosine, 8-oxo-guanosine, 2,N3-ethenoguanosine, and 8-aminoguanosine.
Interestingly, neither WO 98/18324 nor U.S. Pat. No. 6,063,628 contain any data from experiments performed by the inventors to support the claims made therein. Only one experiment is described in which HIV is passaged in vitro in the presence of either 5-hydroxyuridine or 5-bromocytidine. The results after 4 passages are shown in FIG. 3: no decline in viral titer is apparent in the Figures.
The content of all documents mentioned in this specification is incorporated herein by reference.